WO2011099507A1 - Sel de dérivé hétérocyclique condensé et cristal de celui-ci - Google Patents

Sel de dérivé hétérocyclique condensé et cristal de celui-ci Download PDF

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WO2011099507A1
WO2011099507A1 PCT/JP2011/052719 JP2011052719W WO2011099507A1 WO 2011099507 A1 WO2011099507 A1 WO 2011099507A1 JP 2011052719 W JP2011052719 W JP 2011052719W WO 2011099507 A1 WO2011099507 A1 WO 2011099507A1
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compound
sex hormone
compound according
dependent
pharmaceutical composition
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PCT/JP2011/052719
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English (en)
Japanese (ja)
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一道 城
竹内　秀樹
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キッセイ薬品工業株式会社
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Priority to ES11742250.1T priority Critical patent/ES2502740T3/es
Priority to JP2011553858A priority patent/JP5337261B2/ja
Application filed by キッセイ薬品工業株式会社 filed Critical キッセイ薬品工業株式会社
Priority to SG2012059002A priority patent/SG183243A1/en
Priority to NZ601684A priority patent/NZ601684A/xx
Priority to BR112012020110-7A priority patent/BR112012020110B1/pt
Priority to AU2011215250A priority patent/AU2011215250B2/en
Priority to MX2012009323A priority patent/MX2012009323A/es
Priority to RU2012138445/04A priority patent/RU2557237C2/ru
Priority to CN201180009003.6A priority patent/CN102753557B/zh
Priority to CA2788533A priority patent/CA2788533C/fr
Priority to KR1020127021797A priority patent/KR101631143B1/ko
Priority to EP11742250.1A priority patent/EP2535342B1/fr
Priority to US13/577,832 priority patent/US9169266B2/en
Publication of WO2011099507A1 publication Critical patent/WO2011099507A1/fr
Priority to IL221325A priority patent/IL221325A/en
Priority to US14/867,501 priority patent/US9737539B2/en
Priority to US15/647,911 priority patent/US10016433B2/en
Priority to US16/020,436 priority patent/US10576084B2/en
Priority to US16/747,603 priority patent/US20200390768A1/en
Priority to FR22C1049C priority patent/FR22C1049I2/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/14—Quaternary ammonium compounds, e.g. edrophonium, choline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/16—Masculine contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/02—Drugs for disorders of the endocrine system of the hypothalamic hormones, e.g. TRH, GnRH, CRH, GRH, somatostatin
    • A61P5/04—Drugs for disorders of the endocrine system of the hypothalamic hormones, e.g. TRH, GnRH, CRH, GRH, somatostatin for decreasing, blocking or antagonising the activity of the hypothalamic hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/06—Drugs for disorders of the endocrine system of the anterior pituitary hormones, e.g. TSH, ACTH, FSH, LH, PRL, GH
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/06—Drugs for disorders of the endocrine system of the anterior pituitary hormones, e.g. TSH, ACTH, FSH, LH, PRL, GH
    • A61P5/08—Drugs for disorders of the endocrine system of the anterior pituitary hormones, e.g. TSH, ACTH, FSH, LH, PRL, GH for decreasing, blocking or antagonising the activity of the anterior pituitary hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/62—Quaternary ammonium compounds
    • C07C211/63—Quaternary ammonium compounds having quaternised nitrogen atoms bound to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present invention has a gonadotropin-releasing hormone antagonistic action and has sex such as prostatic hypertrophy, uterine fibroids, endometriosis, uterine fibroma, precocious puberty, amenorrhea, premenstrual syndrome, dysmenorrhea, etc.
  • sex such as prostatic hypertrophy, uterine fibroids, endometriosis, uterine fibroma, precocious puberty, amenorrhea, premenstrual syndrome, dysmenorrhea, etc.
  • Sex hormone-dependent diseases such as prostatic hypertrophy, uterine fibroids, endometriosis, uterine fibroma, precocious puberty, amenorrhea, premenstrual syndrome, dysmenorrhea Useful as a prophylactic or therapeutic agent for:
  • compound (B) (Hereinafter referred to as “compound (B)”) is disclosed in Patent Document 1.
  • the salt there is only a general description as a pharmacologically acceptable salt, and the salt of the compound (B) is not specifically reported.
  • the compound (B) described in Patent Document 1 is amorphous or crystalline.
  • Amorphous materials for example, are difficult to isolate and purify with a certain quality on an industrial scale, and crystals are generally desired as drug substances.
  • the crystal of compound (B) has a problem in solubility as described in the following test example (saturated solubility test). When the solubility is poor, the drug absorbability often becomes a problem, and formulation-like devices may be required for use as a medicine. Therefore, in order to use the compound (B) as a drug substance, an improvement in solubility is required. *
  • the present invention (1) a compound represented by the formula (A); (2) The compound according to (1), which is crystalline; (3) In the powder X-ray diffraction diagram, the diffraction angle (2 ⁇ (°)) is 7.1, 11.5, 19.4, 20.3, 21.5, 22.0, 22.6, 23.5. And the compound according to (2) above, which has a characteristic peak at 26.2; (4) In the 13 C solid state NMR spectrum chart, the chemical shift values ( ⁇ (ppm)) are 155.8, 149.8, 145.3, 118.0, 113.7, 111.6, 110.3, 98. 1.
  • a pharmaceutical composition comprising the compound according to any one of (1) to (6) as an active ingredient; (8) The pharmaceutical composition according to the above (7), which is a gonadotropin releasing hormone antagonist; (9) The pharmaceutical composition according to (7), which is a preventive or therapeutic agent for sex hormone-dependent diseases, a reproductive regulator, a contraceptive, an ovulation inducer, or a preventive agent for sex hormone-dependent cancer postoperative recurrence; (10) The above (1) to (6) for producing a preventive or therapeutic agent for sex hormone-dependent diseases, a reproductive regulator, a contraceptive, an ovulation inducer, or a preventive agent for sex hormone-dependent cancer postoperative recurrence Use of a compound according to any one.
  • (11) A method for preventing or treating a sex hormone-dependent disease, a method for regulating reproduction, a method for contraception, a ovulation induction, which comprises administering an effective amount of the compound according to any one of (1) to (6) above Or a method for preventing recurrence after surgery for sex hormone-dependent cancer.
  • the compound (A) of the present invention has very good solubility and oral absorption. In addition, it has extremely good crystallinity, is excellent in storage stability and fluidity, and is, for example, a compound that is easy to handle in formulation.
  • the compound (A) of the present invention can be produced, for example, by the following method. That is, for example, a compound (B) which is a free form that can be produced according to the method described in Patent Document 1 or a method based thereon, and an equivalent amount (1.0 equivalent) or a small excess amount of choline hydroxide in an appropriate solvent. It can be produced by isolating the precipitated compound (A) by mixing in the solution and dissolving under heating, then concentrating or adding a solvent as necessary, and cooling. Furthermore, the compound (A) can also be purified by recrystallization using the same solvent.
  • the solvent may be any solvent that does not interfere with salt formation.
  • alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol and 2-butanol, ethers such as tetrahydrofuran and diisopropyl ether, etc.
  • ethers such as tetrahydrofuran and diisopropyl ether, etc.
  • the compound (A) of the present invention contains prostatic hypertrophy, uterine fibroids, endometriosis, uterine fibroma, precocious puberty, amenorrhea, premenstrual syndrome, dysmenorrhea, polycystic ovary syndrome, erythematous Sex hormone-dependent diseases such as lupus, hirsutism, dwarfism, sleep disorders, acne, baldness, Alzheimer's disease, infertility, irritable bowel syndrome, prostate cancer, uterine cancer, ovarian cancer, breast cancer, pituitary tumor It is extremely useful as a prophylactic or therapeutic agent, a reproductive regulator, a contraceptive, an ovulation inducer, a prophylactic agent for sex hormone-dependent cancer postoperative recurrence, and the like.
  • a pharmaceutical composition can be prepared by appropriately mixing the compound (A) according to the present invention and a commonly used pharmaceutical carrier.
  • the pharmaceutical carrier may be used in appropriate combination depending on the dosage form described later.
  • excipients such as lactose; lubricants such as magnesium stearate; disintegrants such as carboxymethylcellulose; hydroxypropylmethylcellulose and the like Binding agent; Surfactant such as macrogol; Foaming agent such as sodium bicarbonate; Solubilizing agent such as cyclodextrin; Acidity agent such as citric acid; Stabilizer such as sodium edetate; pH adjustment such as phosphate Agents and the like.
  • Examples of the administration form of the pharmaceutical composition according to the present invention include oral administration agents such as powders, granules, fine granules, dry syrups, tablets and capsules; parenteral administrations such as injections, patches and suppositories.
  • oral administration agents such as powders, granules, fine granules, dry syrups, tablets and capsules
  • parenteral administrations such as injections, patches and suppositories.
  • An oral administration agent is preferable.
  • the above-mentioned preparation is preferably produced so that the compound (A) according to the present invention is administered in the range of 0.1 to 1000 mg for oral administration and 0.01 to 100 mg for injection per day for an adult.
  • Example 1 Compound (A) 3- [2-Fluoro-5- (2,3-difluoro-6-methoxybenzyloxy) -4-methoxyphenyl] -2,4-dioxo-1,2,3,4-tetrahydrothieno [3,4 d] Pyrimidine-5-carboxylic acid (3.07 g) and 46% aqueous choline hydroxide solution (1.64 g) were suspended in a mixed solution (30 mL) of about 1: 1 (volume ratio) of 1-propanol and water, The mixture was heated and stirred at 60 ° C. for 15 minutes.
  • the precipitated crystals were collected by filtration and washed twice with a mixed solvent (1 mL) of about 3 to 1 (volume ratio) of 1-propanol and water. The obtained crystals were air-dried for 4 days to obtain Compound (A) (2.16 g).
  • the powder X-ray diffraction was measured by using a powder X-ray diffractometer X'Pert Pro MPD (Spectris Co., Ltd., Panalical Division) (reflection method; CuK ⁇ ray, tube voltage 45 kV, tube) Current 40 mA).
  • the obtained diffractogram is shown in FIG.
  • the 2 ⁇ value and the overall diffraction pattern are important when identifying the identity of crystals due to the nature of the data. It is generally known that the relative intensity in an X-ray diffraction pattern can vary depending on sample conditions and measurement conditions. Note that the 2 ⁇ value of the diffraction pattern by powder X-ray diffraction may slightly vary depending on the sample conditions and measurement conditions.
  • the 13 C solid state NMR spectrum filling the specimen 4 mm zirconia rotor, using a Bruker Avance DRX500 (rotational speed 10 kHz), were measured by CP / MAS method.
  • the obtained spectrum chart is shown in FIG.
  • the chemical shift value by a 13 C solid state NMR spectrum may fluctuate slightly depending on sample conditions and measurement conditions.
  • the specimen was packed in a 2.5 mm zirconia rotor and measured by the MAS method using an Avance III 400 WideBore (rotation speed 30 kHz) manufactured by Bruker.
  • the spectra were referenced using an external standard sample of polyvinylidene fluoride (PVDF) whose resonance was set at ⁇ 91.2 ppm.
  • PVDF polyvinylidene fluoride
  • the obtained spectrum chart is shown in FIG.
  • the chemical shift value by a 19 F solid state NMR spectrum may fluctuate slightly depending on sample conditions and measurement conditions.
  • Test Example 1 Saturation solubility test The compound (A) obtained in Example 2, the crystal of the compound (B) obtained in Comparative Example 2 and the compound (C) obtained in Comparative Example 3 were mixed with water, 15th revised Japanese Pharmacopoeia General Test Method.
  • the suspension was suspended in the first solution (hereinafter referred to as “first solution”) or the second solution (hereinafter referred to as “second solution”) described in the above-mentioned reagents and test solutions, and incubated at 37 ° C. A part of the suspension was filtered, and the concentration of the obtained filtrate was measured by HPLC, and the saturation solubility was calculated and compared.
  • the measurement conditions by HPLC are as follows.
  • Measurement condition detector UV-visible spectrophotometer / wavelength: 225 nm
  • Constant temperature flow rate 1.0 mL / min
  • Mobile phase A Liquid mobile phase adjusted to pH 5.5 with 10 mM potassium dihydrogen phosphate aqueous solution with potassium hydroxide aqueous solution
  • Table 2 shows the values of the compound (A), the crystal of the compound (B), and the saturation solubility of the compound (C) in water, the first liquid or the second liquid.
  • Compound (A) was found to have a saturation solubility of about 600 times that of Compound (B) crystals and about 60 times that of Compound (C) in water.
  • a saturation solubility of about 30 times with respect to the crystal of the compound (B) and about 2 times with respect to the compound (C) was observed.
  • a saturation solubility of about 10 times with respect to the crystal of the compound (B) and about 70 times with respect to the compound (C) was observed. From the above, in Compound (A), a remarkable improvement in solubility was observed for Compound (B) crystals and Compound (C).
  • Test Example 2 Oral absorbability confirmation test 1 Preparation of specimen for measurement of drug concentration by tail vein administration SD rats (Charles River, male 7 weeks old, 170-210 g) fasted overnight were used as experimental animals. Add 1 mL of compound (B) at a ratio of 0.2 mL of N, N-dimethylacetamide, 0.798 mL of physiological saline, and 0.002 mL of 2N NaOH to prepare a 1.0 mg / mL solution. (3 cases) at a dose of 1 mg / kg under the unanesthetized tail vein. Caudal vein administration was performed using a 26G needle and a 1 mL syringe.
  • Blood was collected from an unanesthetized subclavian vein at 15, 30, 60, 120, 240, 360, and 480 minutes after oral administration. The blood was centrifuged, and plasma was used as a sample for measuring blood drug concentration. 3) Measurement of drug concentration 0.10.0 mL of a solution of an appropriate internal standard substance was added to 0.025 mL of the plasma obtained in 1) and 2) according to a conventional method, and then 0.875 mL of acetonitrile was added to perform protein removal. It was. After centrifugation, 0.005 mL of the supernatant was injected into LC-MS / MS. Plasma drug concentration was measured by the LC-MS / MS method under the following conditions. A calibration curve was prepared by appropriately adding an internal standard substance and a substance to be measured to 0.05 mL of blank plasma according to a conventional method and operating in the same manner as described above.
  • the bioavailability of the compound (A) was about 59%, and good oral absorbability was observed.
  • the maximum blood drug concentration time (Tmax) of compound (B) is 200 minutes, whereas the maximum blood drug concentration time (Tmax) of compound (A) is 35 minutes. Since A) is rapidly absorbed after administration, rapid onset of action is expected. *
  • the bioavailability (%) was determined from the blood drug concentration obtained by the above method using the WinNonlin® Professional (manufactured by Pharsight Corporation) in the tail vein and compound (A) or compound (B). ) was orally administered from the value of the area under the blood drug concentration-time curve.
  • Test Example 3 Stability test The compound (A) obtained in Example 2 was stored under opening at 90 ° C., and the stability was examined. Regarding the stability, the purity at the start of the specimen and the purity after 8 days were measured by HPLC and compared. The measurement conditions by HPLC are as follows.
  • Measurement condition detector UV-visible spectrophotometer / wavelength: 225 nm
  • Column Inertsil ODS-3 manufactured by GL Sciences, 5 ⁇ m, 4.6 ⁇ 250 mm Column temperature: around 35 ° C.
  • Constant temperature flow rate 1.0 mL / min
  • Mobile phase A Liquid mobile phase B adjusted to pH 5.5 with 10 mM potassium dihydrogen phosphate aqueous solution with potassium hydroxide aqueous solution B: Acetonitrile 4)
  • Area measurement range 54 minutes from the start of analysis. The area of the peak derived from the blank was excluded from the calculation. The obtained measurement results are shown in Table 5.
  • the compound (A) of the present invention exhibits extremely excellent solubility, oral absorption and storage stability, and has physical properties in the free compound (B). It is an excellent compound that can solve the problem.
  • the compound (A) according to the present invention has excellent solubility and other physical properties, is useful as a drug substance, and is suitable for industrial production of drugs.
  • FIG. 1 is a powder X-ray diffraction pattern of the compound (A) obtained in Example 1.
  • FIG. The vertical axis represents the X-ray diffraction intensity (Counts), and the horizontal axis represents the diffraction angle (2 ⁇ (°)).
  • FIG. 2 is a TG-DTA measurement diagram of the compound (A) obtained in Example 1.
  • the vertical axis (left) shows the weight (%) in the thermogravimetric (TG) curve
  • the vertical axis (right) shows the heat flux ( ⁇ V) in the differential thermal analysis (DTA) curve
  • the horizontal axis shows the temperature (° C.).
  • Show. 3 is a 13 C solid state NMR spectrum chart of the compound (A) obtained in Example 1.
  • the vertical axis represents intensity, and the horizontal axis represents the chemical shift value ( ⁇ (ppm)).
  • 4 is a powder X-ray diffraction pattern of the compound (B) obtained in Comparative Example 1.
  • FIG. The vertical axis represents the X-ray diffraction intensity (Counts), and the horizontal axis represents the diffraction angle (2 ⁇ (°)).
  • FIG. 5 is a 19 F solid state NMR spectrum chart of the compound (A) obtained in Example 1.
  • the vertical axis represents intensity, and the horizontal axis represents the chemical shift value ( ⁇ (ppm)).

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  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne l'amélioration de la solubilité d'un acide 3-[2-fluoro-5-(2,3-difluoro-6-méthoxybenzyloxy)-4-méthoxyphényl]-2,4-dioxo-1,2,3,4-tétrahydrothiéno[3,4-d]pyrimidine-5-carboxylique. La présente invention concerne un sel de choline représenté par la formule (A), qui a une excellente solubilité et une excellente stabilité à la conservation.
PCT/JP2011/052719 2010-02-10 2011-02-09 Sel de dérivé hétérocyclique condensé et cristal de celui-ci WO2011099507A1 (fr)

Priority Applications (19)

Application Number Priority Date Filing Date Title
KR1020127021797A KR101631143B1 (ko) 2010-02-10 2011-02-09 축합 복소환 유도체의 염 및 그 결정
CA2788533A CA2788533C (fr) 2010-02-10 2011-02-09 Sel de choline de derive heterocyclique fusionne et compositions pharmaceutiques en renfermant
EP11742250.1A EP2535342B1 (fr) 2010-02-10 2011-02-09 Sel de dérivé hétérocyclique condensé et cristal de celui-ci
JP2011553858A JP5337261B2 (ja) 2010-02-10 2011-02-09 縮合複素環誘導体の塩及びその結晶
BR112012020110-7A BR112012020110B1 (pt) 2010-02-10 2011-02-09 composto derivado heterocíclico fusionado, composição farmacêutica que compreende o mesmo e uso terapêutico do dito composto
AU2011215250A AU2011215250B2 (en) 2010-02-10 2011-02-09 Salt of fused heterocyclic derivative and crystal thereof
MX2012009323A MX2012009323A (es) 2010-02-10 2011-02-09 Sal de derivado heterociclico condensado y cristal del mismo.
RU2012138445/04A RU2557237C2 (ru) 2010-02-10 2011-02-09 Соль конденсированного гетероциклического производного и его кристаллы
CN201180009003.6A CN102753557B (zh) 2010-02-10 2011-02-09 稠合杂环衍生物的盐及其晶体
ES11742250.1T ES2502740T3 (es) 2010-02-10 2011-02-09 Sal de derivado heterocíclico condensado y cristal del mismo
NZ601684A NZ601684A (en) 2010-02-10 2011-02-09 Salt of fused heterocyclic derivative and crystal thereof
SG2012059002A SG183243A1 (en) 2010-02-10 2011-02-09 Salt of fused heterocyclic derivative and crystal thereof
US13/577,832 US9169266B2 (en) 2010-02-10 2011-02-09 Salt of fused heterocyclic derivative and crystal thereof
IL221325A IL221325A (en) 2010-02-10 2012-08-06 Salt of compressed heterocyclic sequela and its crystal
US14/867,501 US9737539B2 (en) 2010-02-10 2015-09-28 Salt of fused heterocyclic derivative and crystal thereof
US15/647,911 US10016433B2 (en) 2010-02-10 2017-07-12 Salt of fused heterocyclic derivative and crystal thereof
US16/020,436 US10576084B2 (en) 2010-02-10 2018-06-27 Salt of fused heterocyclic derivative and crystal thereof
US16/747,603 US20200390768A1 (en) 2010-02-10 2020-01-21 Salt of fused heterocyclic derivative and crystal thereof
FR22C1049C FR22C1049I2 (fr) 2010-02-10 2022-09-26 Sel de derive heterocyclique condense et cristal de celui-ci

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JP2010027806 2010-02-10

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US14/867,501 Division US9737539B2 (en) 2010-02-10 2015-09-28 Salt of fused heterocyclic derivative and crystal thereof
US14/867,501 Continuation US9737539B2 (en) 2010-02-10 2015-09-28 Salt of fused heterocyclic derivative and crystal thereof

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BR (1) BR112012020110B1 (fr)
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WO2014042176A1 (fr) * 2012-09-14 2014-03-20 キッセイ薬品工業株式会社 Procédé de production d'un dérivé hétérocyclique fusionné, et production intermédiaire
WO2018030317A1 (fr) * 2016-08-08 2018-02-15 キッセイ薬品工業株式会社 Administration et dosage d'un agent thérapeutique pour l'endométriose
JP2020522525A (ja) * 2017-06-05 2020-07-30 オブセヴァ エス．エー． 子宮筋腫を治療し、月経失血を低下させるゴナドトロピン放出ホルモンアンタゴニスト投与計画
CN115232144A (zh) * 2021-04-22 2022-10-25 长春金赛药业有限责任公司 含氮稠环类衍生物、药物组合物及其制备方法和应用
WO2023149546A1 (fr) * 2022-02-04 2023-08-10 キッセイ薬品工業株式会社 Préparation solide orale
US11980621B2 (en) 2017-06-05 2024-05-14 Kissei Pharmaceutical Co., Ltd. Gonadotropin-releasing hormone antagonist dosing regimens for the treatment of endometriosis

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CA3117092A1 (fr) 2018-10-29 2020-05-07 ObsEva S.A. Compositions et methodes de traitement de l'endometriose interne et de l'endometriose rectovaginale
EP3876943A2 (fr) 2018-11-07 2021-09-15 ObsEva S.A. Compositions et méthodes de traitement de troubles dépendant des oestrogènes
KR20220061120A (ko) 2019-08-08 2022-05-12 옵스에파 에스에이 에스트로겐-의존성 장애 치료용 조성물 및 방법
KR20220045198A (ko) * 2019-08-08 2022-04-12 옵스에파 에스에이 에스트로겐-의존성 장애의 치료를 위한 gnrh 길항제
WO2024049275A1 (fr) * 2022-09-02 2024-03-07 Rexpharmtech Co., Ltd Nouveau sel de benfotiamine choline

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Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014042176A1 (fr) * 2012-09-14 2014-03-20 キッセイ薬品工業株式会社 Procédé de production d'un dérivé hétérocyclique fusionné, et production intermédiaire
JPWO2014042176A1 (ja) * 2012-09-14 2016-08-18 キッセイ薬品工業株式会社 縮合複素環誘導体の製造方法およびその製造中間体
TWI746613B (zh) * 2016-08-08 2021-11-21 日商橘生藥品工業股份有限公司 子宮內膜病症治療劑之用法及用量
AU2017309015B2 (en) * 2016-08-08 2022-09-15 Kissei Pharmaceutical Co., Ltd. Administration and dosage of therapeutic agent for endometriosis
KR20190037225A (ko) 2016-08-08 2019-04-05 깃세이 야쿠힌 고교 가부시키가이샤 자궁내막증 치료제의 용법·용량
JPWO2018030317A1 (ja) * 2016-08-08 2019-06-13 キッセイ薬品工業株式会社 子宮内膜症治療剤の用法・用量
US10646491B2 (en) 2016-08-08 2020-05-12 Kissei Pharmaceutical Co., Ltd. Usage and dosage of therapeutic agents for endometriosis
IL264554A (en) * 2016-08-08 2019-02-28 Kissei Pharmaceutical Use and dosage of therapeutic agents for endometrial disease
WO2018030317A1 (fr) * 2016-08-08 2018-02-15 キッセイ薬品工業株式会社 Administration et dosage d'un agent thérapeutique pour l'endométriose
EA039240B1 (ru) * 2016-08-08 2021-12-22 Киссеи Фармасьютикал Ко., Лтд. ПРИМЕНЕНИЕ ФАРМАЦЕВТИЧЕСКОЙ КОМПОЗИЦИИ, СОДЕРЖАЩЕЙ 3-[2-ФТОР-5-(2,3-ДИФТОР-6-МЕТОКСИБЕНЗИЛОКСИ)-4-МЕТОКСИФЕНИЛ]-2,4-ДИОКСО-1,2,3,4-ТЕТРАГИДРОТИЕНО[3,4-d]ПИРИМИДИН-5-КАРБОНОВУЮ КИСЛОТУ ИЛИ ЕЁ ФАРМАЦЕВТИЧЕСКИ ПРИЕМЛЕМУЮ СОЛЬ, В СПОСОБЕ ЛЕЧЕНИЯ ЭНДОМЕТРИОЗА
US11382914B2 (en) 2016-08-08 2022-07-12 Kissei Pharmaceutical Co., Ltd. Usage and dosage of therapeutic agents for endometriosis
JP2020522525A (ja) * 2017-06-05 2020-07-30 オブセヴァ エス．エー． 子宮筋腫を治療し、月経失血を低下させるゴナドトロピン放出ホルモンアンタゴニスト投与計画
JP7292566B2 (ja) 2017-06-05 2023-06-19 キッセイ薬品工業株式会社 子宮筋腫を治療し、月経失血を低下させるゴナドトロピン放出ホルモンアンタゴニスト投与計画
US11759464B2 (en) 2017-06-05 2023-09-19 Kissei Pharmaceutical Co., Ltd. Gonadotropin-releasing hormone antagonist dosing regimens for treating uterine fibroids and reducing menstrual blood loss
US11980621B2 (en) 2017-06-05 2024-05-14 Kissei Pharmaceutical Co., Ltd. Gonadotropin-releasing hormone antagonist dosing regimens for the treatment of endometriosis
JP7485815B2 (ja) 2017-06-05 2024-05-16 キッセイ薬品工業株式会社 子宮筋腫を治療し、月経失血を低下させるゴナドトロピン放出ホルモンアンタゴニスト投与計画
CN115232144A (zh) * 2021-04-22 2022-10-25 长春金赛药业有限责任公司 含氮稠环类衍生物、药物组合物及其制备方法和应用
CN115232144B (zh) * 2021-04-22 2024-04-02 长春金赛药业有限责任公司 含氮稠环类衍生物、药物组合物及其制备方法和应用
WO2023149546A1 (fr) * 2022-02-04 2023-08-10 キッセイ薬品工業株式会社 Préparation solide orale

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TW201144319A (en) 2011-12-16
US20160082010A1 (en) 2016-03-24
JPWO2011099507A1 (ja) 2013-06-13
KR20130002984A (ko) 2013-01-08
NZ601684A (en) 2013-08-30
JP5337261B2 (ja) 2013-11-06
US9169266B2 (en) 2015-10-27
CA2788533C (fr) 2018-03-06
AU2011215250B2 (en) 2014-07-31
MX2012009323A (es) 2012-11-21
TWI555751B (zh) 2016-11-01
IL221325A0 (en) 2012-10-31
US10016433B2 (en) 2018-07-10
US9737539B2 (en) 2017-08-22
EP2535342A4 (fr) 2013-07-10
CN102753557A (zh) 2012-10-24
EP2535342A1 (fr) 2012-12-19
IL221325A (en) 2016-09-29
RU2557237C2 (ru) 2015-07-20
EP2535342B1 (fr) 2014-08-06
FR22C1049I1 (fr) 2022-12-09
FR22C1049I2 (fr) 2023-11-24
US20130059867A1 (en) 2013-03-07
BR112012020110A2 (pt) 2018-03-20
RU2012138445A (ru) 2014-03-20
BR112012020110B1 (pt) 2021-06-08
US20170319588A1 (en) 2017-11-09
CN102753557B (zh) 2015-10-14
SG183243A1 (en) 2012-09-27
CA2788533A1 (fr) 2011-08-18
KR101631143B1 (ko) 2016-06-17
AU2011215250A1 (en) 2012-09-06
US10576084B2 (en) 2020-03-03
US20190134038A1 (en) 2019-05-09
US20200390768A1 (en) 2020-12-17
ES2502740T3 (es) 2014-10-06

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